Is GP1BA p.Ser486fs (c.1454dup) pathogenic?

GP1BA p.Ser486fs (c.1454dup) is classified Pathogenic in GP1BA (ClinVar, Expert panel, 3 submitters; last evaluated 2025-02-11). Very rare (popmax 0.00268%, afr); Associated with Bernard-Soulier syndrome.

What condition is associated with GP1BA p.Ser486fs (c.1454dup)?

GP1BA p.Ser486fs (c.1454dup) is associated with Bernard-Soulier syndrome (ClinVar).

How common is GP1BA p.Ser486fs (c.1454dup) in the general population?

GP1BA p.Ser486fs (c.1454dup) is very rare (popmax 0.00268%, afr) (gnomAD).

How is Bernard-Soulier syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GP1BA p.Ser486fs

c.1454dup · rs774388410 · VCV2137887

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

Bernard-Soulier syndrome

ClinGen expert panel — Platelet Disorders VCEP

Pathogenic for Bernard-Soulier syndrome. Applied ACMG criteria (verbatim):

PVS1_Strong PM2_Supporting PS3_Supporting PM3_Strong PP1 PP4

Curation rationale (ClinGen, verbatim)

NM_000173.7(GP1BA):c.1454dup is a frameshift variant (p.Ser486IlefsTer12), which has been reported in multiple probands with Bernard-Soulier syndrome (PMIDs:11776304, 16916536, 23402648, 24934643, 9241731). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000004440 (based on 2/74766) in the African/African American population, which does not meet PM2_supporting or BS1. The frameshift variant may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove 24% of the protein (PVS1_Strong). Case 2 of PMID: 9241731 is compound heterozygous with c.1480del (classified Pathogenic by the PD-VCEP) confirmed in trans and at least two additional patients are homozygous for the variant (PM3_strong). At least one patient (Proband in PMID:11776304) with this variant had aggregation absent for ristocetin but present for all other agonists and flow cytometry with less than 10% expression of GPIBa (PP4). The variant segregated with Bernard-Soulier syndrome in this patient plus an affected sibling, both compound heterozygous for this variant and Cys225Ser (PP1). Finally, surface expression of GP1Balpha measured by flow cytometry from transient transfection of the c.1454dup variant in CHO cells stably co-expressing the GPIbbeta and GPIX subunits showed decreased expression at 0% (<25%) WT levels, indicating that this variant impacts protein function (PMID:11776304; PS3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM3_strong, PS3_supporting, PVS1_strong, PP4, PM2_supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.12	GERP -2.4
Overall
CADD	19.24	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,766 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,254 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,383
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	8.48e-05%	1,179,862

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GP1BA
Protein: p.Ser486fs
Coding: c.1454dup
MANE Select: NM_000173
dbSNP: rs774388410
Type: Duplication
Location: chr17:4934057 (GRCh38)
Gene constraint: LOEUF 1.289 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 64.65 · 22 PDB

Full GP1BA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bernard-Soulier syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bernard-Soulier syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

GP1BA p.Ser486Ter Likely pathogenic ★★★ same residue
GP1BA p.Asn362fs Likely pathogenic ★★★ same condition
GP1BA p.Asp79fs Likely pathogenic ★★★ same condition
GP1BA p.Asp89fs Likely pathogenic ★★★ same condition
GP1BA p.Leu479fs Likely pathogenic ★★★ same condition
GP1BA p.Leu52fs Likely pathogenic ★★★ same condition
GP1BA p.Met338fs Likely pathogenic ★★★ same condition
GP1BA p.Pro357fs Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gp1ba-p-ser486fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown